My overall goal is to acquire both the didactic training and practical laboratory experience necesary to become an independent biomedical investigator. I plan to apply this training to studies of the contribution of collagen gene alterations to a variety of hereditary disorders, including selected heritable disorders of fibrous connective tissue and chondrodystrophies. The following approaches are proposed: (1) The structure and organization of the various collagen genes in these disorders will be determined by Southern blot analysis. Unusual patterns will be compared to those seen in a panel of controls to determine if the former are the result of gross gene alterations. (2) More subtle alterations in the structure of collagen genes will be detected by linkage analysis. Large families with multiple affected individuals will be examined for cosegregation of the "mutant" phenotype and a specific collagen allele whose inheritance is detected by polymorphic restriction sites. (3) In individuals or families in whom either (1) or (2) indicates mutation in a collagen gene, studies of mRNA and protein encoded by this gene will be performed to investigate the functional significance of the gene alteration, and the mutant gene will be cloned and sequenced to demonstrate the nature of the mutation. (4) For those collagen loci for which the chromosomal assignment is unknown or unconfirmed, such assignments will be undertaken. (5) The genetic distance between the various collagen genes studies in (1)\and (2) and selected syntenic loci will be determined. The purpose of these studies is four-fold: (i) to identify and characterize mutations in the collagen genes which are responsible for certain familial disorders of connective tissues, (ii) to determine the effect of such mutations on collagen mRNA and protein synthesis and structure; (iii) to identify normal variations in the structure and organization of the collagen genes as revealed by restriction fragment length polymorphisms; (iv) to add to our knowledge of the human gene map, both in terms of the chromosomal localization of and the genetic distances between closely linked loci and the various collagen genes.